Objectives: To examine the relative effectiveness of hormonal and central nervous system medications in treating severe premenstrual syndrome. These comparisons, using data from double-blind, placebo-controlled, and open-label trials, provide information on the clinical effectiveness of the medications and insight into the relative importance of hormonal and CNS effects in PMS treatment. Study design: In a series of studies, includinb both open label and the largest double-blind, placebo-controlled, randomized studies of treatment to date, we examined the benzodiazepine alprazolam compared with oral micronized progesterone and placebo (n = 170), progesterone suppository treatment (n = 168), the GnRH agonist leuprolide acetate depot (n = 30), antidepressant medications including desipramine (n = 10) and the new serotonergic drugs: nefazodone (n = 47), sertraline (n = 20), fluvoxamine (n = 10), and fluoxetine (n = 10). All treatment groups met the same PMS criteria, all had the same primary outcome measure of the Daily Symptom Report, and all were treated for a similar time period of 2-3 months. Changes in total premenstrual symptoms and symptom clusters from baseline were examined to provide insight into the extent of reduction in total symptoms and symptom clusters. Side effect profiles and the effects of comorbidity of depression on treatment outcome were also compared. Results: Alprazolam is more effective than a placebo in reducing premenstrual symptoms. Oral micronized progesterone is not effective, as was previously found for progesterone suppository treatment. GnRH analogs effectively reduce PMS symptoms but not the depression symptoms in women with comorbidity of major depression. The serotonergic antidepressants significantly reduce symptoms both in PMS and in premenstrual exacerbation of major depression. Conclusions: The serotonergic drugs appear to be a promising and well-tolerated treatment for premenstrual symptoms. Progesterone appears to have no clinically significant effect as a treatment to reduce PMS symptoms. However, the remission of symptoms that is obtained by suppression of the gonadal hormones suggests their still-unidentified involvement in PMS symptomatology.